Metabolism and Disposition of [¹⁴C]BMS-690514 after Oral Administration to Rats, Rabbits, and Dogs

Abstract

]BMS-690514 to rats and dogs, the majority of the radioactive dose (61-71%) was recovered in the feces, whereas 18 to 20% was eliminated in urine. In bile duct-cannulated rats, 83 and 17% of the administered radioactivity was recovered in the bile and urine, respectively, suggesting that biliary secretion was a major route for the elimination of BMS-690514-derived radioactivity in rats.The parent compound underwent extensive metabolism in both species, with <12% of the administered radioactivity recovered as BMS-690514 in the excreta samples. Metabolite profiles in plasma were qualitatively similar in rats, rabbits, and dogs. Unchanged BMS-690514 was a prominent drug-related component in the plasma profiles from all the species. However, multiple metabolites contributed significantly to the circulating radioactivity, particularly for rabbit and dog, in which metabolites comprised 73 to 93% of the area under the time curve (0-8 h). Circulating metabolites included M6, a direct Oglucuronide conjugate; M1, a hydroxylated metabolite; and glucuronide conjugates of hydroxylated and O-demethylated metabolites. Overall, the results from these studies suggested that BMS-690514 was well absorbed and highly metabolized through multiple pathways in these preclinical species.

Rearrangement reactions catalyzed by cytochrome P450s

“…A similar type of condensation has been observed in the cytochrome P450-catalyzed oxidation and rearrangement of an amino pyrrolotriazine drug candidate (Fig. 30) [82]. …”

Mechanistic Studies on a P450-Mediated Rearrangement of BMS-690514: Conversion of a Pyrrolotriazine to a Hydroxypyridotriazine

“…M1 was a prominent circulating metabolite found in the plasma of rats, rabbits, dogs, and humans after the administration of BMS-690514 , . M37, also present in these four species, was the precursor of a prominent O -glucuronide conjugate, M7 .…”

“…In vitro experiments suggested that direct glucuronidation and CYP2D6 and CYP3A4-mediated oxidation were likely to be important pathways in the metabolism of BMS-690514 . In vivo, BMS-690514 was well absorbed and highly metabolized in rats, dogs, and humans , . The primary metabolic pathways of this compound included hydroxylation, O -demethylation, and glucuronidation , (Figure ).…”

“…In vivo, BMS-690514 was well absorbed and highly metabolized in rats, dogs, and humans , . The primary metabolic pathways of this compound included hydroxylation, O -demethylation, and glucuronidation , (Figure ). The structural elucidation and detailed analytical characterization for important metabolites has been reported previously , .…”

“…The primary metabolic pathways of this compound included hydroxylation, O -demethylation, and glucuronidation , (Figure ). The structural elucidation and detailed analytical characterization for important metabolites has been reported previously , . Although the structures of M1 and M37 were also disclosed , detailed experiments to characterize these two metabolites have not been published.…”